The incidence of fungal infections and the emergence of opportunistic fungal infections are increasing (Hajjeh et al., J Clin Microbiol, 42:1519-1527 (2004); Walsh et al., Clin Microbiol Infect, 10 (Suppl.1):48-66 (2004)). The increase in immunocompromised patients due to diseases (e.g., AIDS, cancer, organ transplants), and use of medical devices (Kojic et al., Clin Microbiol Rev, 17(2):255-267 (2004)) contribute to the substantial increase in the occurrence of serious fungal infections. The limited number of effective and non-toxic antifungals and the emergence of resistance highlight the need for alternative antifungals. For example, candidiasis is a major nosocomial infection in immunocompromised patients and the most common hospital-acquired mycosis (Rees et al., Clin Infect Dis, 27:1138-1147 (1998)). Griseofulvin, introduced in 1958, was the first available drug for the treatment of severe systemic mycoses; amphotericin B was introduced in 1960 and remains the mainstay therapy for serious Candida infections (Gupta et al., J Am Acad Dermatol, 30:677-698 (1994)). However, the clinical utility of Amphotericin B is hampered by dose-limiting nephrotoxicity (Sabra et al., Drug Saf, 5:94-108 (1990); Dismukes, Clin Infect Dis, 30:653-657 (2000)). Fluconazole provides new options for invasive candidiasis, but the emergence of resistance poses some problems (Müller et al., J Antimicrob Chemother, 46:338-341 (2000)).
Thus, new classes of antifungal agents such as the candins (pneumocandins, echinocandins), the nikkomycins, and the pradamicins-benanomicins were developed (Ghannoum et al., Clin Microbiol Rev, 12:501-517 (1999)). The echinocandins are semisynthetic lipopeptide compounds targeted to the fungal cell wall, particularly the biosynthesis of 1,3-β-D-glucan. Cilofungin (N-p-octyloxybenzoylechinocandin B nucleus), the first echinocandin developed for clinical trials, has excellent in vitro an in vivo activity against disseminated candidiasis (Perfect et al., Antimicrob Agents Chemother, 33:1811-1812 (1989)); however, clinical development of cilofungin was discontinued because of toxicity (Walsh et al., Clin Infect Dis, 14 (Suppl. 1):139-147 (1992)). An improved echinocandin, Eraxis (anidulafungin: echinocandin B nucleus with a terphenyl head group and a C5 tail), was most recently approved by the FDA against life-threatening bloodstream Candida infections. Eraxis administered by injection is indicated for candidemia, peritonitis (infection of the abdominal cavity and intra-abdominal abscesses), and esophageal candidiasis (relapse rates post-therapy were higher for patients on Eraxis). Eraxis has not been studied in endocarditis, osteomyclitis, and meningitis due to Candida, and has not been studied in sufficient numbers of neutropenic patients (low white blood cell counts) to determine efficacy (Benjamin et al., Antimicrob Agents Chemother, 50(2):632-663 (2006)).
Leading Antifungals:
Amphotericin B. The only fungicidal agent available and remains the ‘gold standard’ for the treatment of most systemic mycoses today (Khoo et al., J Antimicrob Chemother, 33:203-213 (1994)). Amphotericin B is highly hydrophobic and commonly administrated as desoxycholate amphotericin (DAMB), a detergent micelle complex. Amphotericin B is usually administered by intravenous infusion; however, its use is limited by its substantial infusion-related and end organ toxicity (Gallis et al., Rev Infect Dis, 12:308-328 (1990)). Amphotericin B is insoluble in water, which accounts for its toxicity and poor bioavailability. Thus, new lipid-based formulations have been developed (Graybill, Ann Inter Med, 1245:921-923 (1996)): Abelcet (ABLC, amphotericin B: lipid Complex); Amphocil (ABCD: amphotericin B Colloid Dispersion); and, Ambisome (Liposomal amphotericin B). Each has been shown to be substantially less nephrotoxic than amphotericin B deoxycholate (Tollemar et al., Transplantation, 59:45-50 (1995)). Despite these new lipid formulations, amphotericin B combined with the detergent deoxycholate, still forms the first line therapy for empirical treatment of opportunistic fungal infections with greater in vivo activity and significantly less expensive than liposomal amphotericin B (Pahls et al., J Infect Dis, 169:1057-1061 (1994)).
Azole antifungals: Itraconazole (Sporanox) is the only marketed azole effective against pulmonary or extrapulmonary aspergillosis, particularly for patients refractory or intolerant to amphotericin B (Herbrecht et al., N Engl J Med, 347:408-415 (2002)). Itraconazole is the drug of choice against non-life threatening histoplasmosis, blastomycosis, paraccocidiodomycosis and meningeal coccidioidomycosis; and, the preferred agent for treatment of lymphocutaneous sporotrichosis. In candidemia, fluconazole (Diflucan) remains the drug of choice in neutropenic and non-neutropenic patients. However, amphotericin B is the agent of choice against C. krusei or fluconazole-resistant organism and in patients developing candidemia while on fluconazole therapy (Sheehan et al., Clin Microbial Rev, 12:40-79 (1999); Fidel et al., Clin Microbial Rev, 12(1):80-96 (1999)). In general, the azoles have a broad-spectrum antifungal activities and safer than amphotericin B, but are fungistatic, which lead to resistance and clinical failures.
Echinocandins: The echinocandins are a relatively new class of antifungals introduced some 15 years ago (Denning, J Antimicrob Chemother, 49:889-891 (2002)). The first FDA approved echinocandin product is caspofungin acetate (Cancidas; Merck); subsequent members of the class include micafungin (Mycamine; Fujisawa) and most recently (2/17/2006) anidulafungin (Eraxis; Pfizer). Although the echinocandins, in general, show comparable antifungal activities with the azoles, they have high molecular weights and are lipophilic (poorly soluble in water). Poor water-solubility may explain their poor oral absorption, which limits their utility to intravenous administration; thus, the need to develop water-soluble echinocandins (Hino et al., J Ind Microbiol Biotechnol, 27(3):157-162 (2001)).
Antifungal Therapy with AIDS
AIDS (acquired immune deficiency syndrome) disease is characterized by a gradual deterioration of immune function, particularly the CD4 positive (CD4+) T cells, due to HIV (human immune deficiency virus) infection. A healthy person usually has 800 to 1,200 CD4+ T cells per cubic millimeter (mm 3); once the CD4+ T cell count falls below 200/mm3, an individual becomes vulnerable to opportunistic infections and cancers. The FDA has approved several antifungal agents of different chemical classes (polyenes, pyrimidines, azoles, and echinocandins); however, treatment is often complicated by high toxicity, low tolerability, or narrow spectrum (Dismukes, Clin Infect Dis, 30:653-657 (2000)). Intensive therapy with amphotericin B is the treatment of choice in most situations.
In cryptococcal meningitis, the favored regimen is an “initial therapy” of amphotericin B plus flucytosine (Ancobon) for 2 weeks or until the patient's condition stabilizes, followed by a “consolidative therapy” of itraconazole or fluconazole for another 8-12 weeks (Saag et al., Clin Infect Dis, 30:710-718 (2000)). However, emergence of resistance to fluconazole after long treatments or prophylaxis is a growing concern (Berg et al., Clin Infect Dis, 26:186-187 (1998)), which now requires greater vigilance and more-widespread surveillance (Chandenier et al., J Clin Microbiol Infect Dis, 23:506-508 (2004)). In AIDS patients with extra-meningeal cryptococcosis (such as that of lungs, bone, soft tissue, disseminated form), itraconazole is quite effective, but is not indicated in cryptococcuria (Denning et al., Arch Intern Med, 149(10):2301-2308 (1989)).
In coccidioidal meningitis with AIDS, intrathecal amphotericin B has been the treatment of choice but is associated with compliance/administration problems and high incidence of adverse effects such as neurological toxicity (Stevens et al., Semin Respir Infect, 16:263-269 (2001)). Thus, fluconazole is the best alternative because of easy administration, better CSF penetration and predictable toxicity profile (Galgiani et al., Clin Infect Dis, 30(4):658-661 (2000)). In disseminated histoplasmosis with AIDS, initial intensive amphotericin B is the treatment of choice followed by maintenance therapy with itraconazole (Bartlett, Medical management of HIV infections, 113-137 (1999)); ketoconazole is not advisable for maintenance therapy because of a high failure rate.
Invasive aspergillosis is a serious complication in AIDS patients, and is associated with a poor prognosis (Marr et al., Infect Dis Clin North Am, 16:875-894 (2002)). Amphotericin B remains the drug of choice, though cure is rarely achieved. Itraconazole is indicated in patients intolerant to amphotericin B for maintenance therapy (Dupont, J Am Acad Dermatol, 23:607-614 (1990)), although only half are clinically stable for before succumbing to aspergillosis or another AIDS-related complications (Denning et al., Rev Infect Dis, 12:1147-1201 (1990)). Despite the introduction of newer antifungals (Steinbach et al., Clin Infect Dis, 37:157-187 (2003)), mortality rate associated with invasive aspergillosis remains nearly 100% in some patient groups (Denning, Clin Infect Dis, 23:608-615 (1996)).
Another common fungal infection in AIDS patients is mucosal and invasive candidiasis, especially the oropharyngeal (OPC) and esophageal form. Fluconazole in high doses (400-800 mg/day) remains the drug of choice for treatment (Newman et al., Clin Infect Dis, 19(4):684-686 (1994)); at low doses (150 mg per week), it is effective in preventing relapse. Unfortunately, the widespread use of fluconazole has spawned fluconazole-resistant strains of C. albicans and is a major problem in patients with advanced AIDS (Metzger et al., Mycoses, 40(Suppl. 1):56-63 (1997)). Itraconazole oral suspension have shown good results in AIDS patients with OPC who were clinically resistant to fluconazole (Saag et al., AIDS Res Hum Retroviruses, 15(16):1413-1417 (1999)), and esophageal candidiasis responds to 100 mg/day for at least 3 weeks, including 2 weeks after resolution of symptoms (Wilcox et al., J Infect Dis, 176:227-232 (1997)).
Antifungals and Drug Interaction:
Xenobiotics. Foreign chemicals or drugs are xenobiotics, which are subjected to a detoxification process by the cytochrome P450 (CYP) enzymes: converting lipophilic drugs into water-soluble forms for urine excretion. A drug that inhibits a specific CYP isozyme may decrease the metabolism of the drug and increase serum concentrations of drugs that are substrates for that isoenzyme. Conversely, a drug that induces a specific CYP isozyme may increase the metabolism of the drug and decrease serum concentrations of drugs that are substrates for that isozyme. Interference of drug metabolism by CYP induction, suppression, or inhibition accounts for some of the most common and potentially severe drug interactions encountered in the clinic (Zhou et al., Clin Pharmacokinet, 44(3):279-304 (2005)).
Because of the lipophilic nature of current antifungal drugs, drug interactions can arise with virtually any antifungal therapy, occurring in the gastrointestinal tract, liver and kidneys. Many drug interactions are a result of inhibition or induction of CYP, which changes the absorption or elimination of the interacting drug as well as the antifungal agent (Gubbins et al., Drug Interactions in Infectious Diseases (2001)). In the GI tract, changes in pH, complexation with ions, or interference with transport and enzymatic processes in the intestinal lumen can interfere with drug absorbance. Induction or inhibition of metabolism in the liver can inhibit or accelerate, respectively, drug clearance. In the kidney, decreases in glomerular filtration, active tubular secretion or other mechanisms can slow renal elimination resulting in excessive drug exposure.
The principal site for drug metabolism is the liver where lipophilic compounds are transformed into ionized metabolites for renal elimination (Kashuba et al., Drug Interactions in Infectious Diseases (2001)). The kidneys, usually known for excretion of water, electrolytes, drugs and other chemicals, also are very active in drug biotransformation. The CYP enzyme system in the kidneys has been identified as being as active as that in the liver, when corrected for organ mass. Therefore, patients with severe renal insufficiency receiving chronic drug therapy may experience accumulation of metabolites of some agents as well as the parent compounds.
Amphotericin B has several formidable toxicities, which are divided into 2 broad categories: infusion toxicities (chemical phlebitis, hypoxia, chills, fever, and nausea) and nephrotoxicity (manifested by renal insufficiency, hypokalemia, hypomagnesemia, renal tubular acidosis, and anemia). Nephrotoxicity occurs in as many as 80% of patients on amphotericin B and is enhanced by concomitant use of other nephrotoxic agents such as aminoglycosides, cyclosporine, cisplatin and nitrogen mustard compounds (Gleckman, Infect Dis Clin North Am, 9(3):575-590 (1995)).
All of the azole-class antifungals currently licensed by the FDA are metabolized to some degree by the CYP P450 system. Antifungal imidazole derivatives are frequently used both systemically and topically (depending on the particular agent) in the treatment of systemic candidal infections and mycoses. These derivatives, including ketoconazole (Nizoral), miconazole, tioconazole (Vagistat-1), clotrimazole (Lotrimin, Mycelex), and sulconazole (Exelderm), are recognized as potent ligands of the heme iron atom of P450s (Katz, Br J Dermatol, 141(Supp156):26-32 (1999)). Ketoconazole and itraconazole are weak bases, virtually insoluble in water, and are ionized only at a low pH. Consequently, dissolution and absorption of these compounds is heavily dependent on acidic gastric conditions in the stomach (Lange et al., J Clin Pharmacol, 37:535-540 (1997)). Drugs that increase gastric pH (e.g., H2 antagonists, proton pump inhibitors) slow the dissolution of the solid dosage forms and decrease drug available for absorption in the intestinal lumen. Because the azole drugs are metabolized by the hepatic cytochrome P-450 system, a variety of interactions can occur between these agents and other medications. The azole antifungals decrease the catabolism of numerous drugs resulting in increased serum concentrations of these medications and the potential for drug toxicity (e.g., histamine H1 receptor antagonists, warfarin, cyclosporin, tacrolimus, sirolimus, digoxin, felodipine, lovastatin, midazolam, triazolam, methylprednisolone, glibenclamide, rifabutin, ritonavir, saquinavir, nevirapine, nortriptyline, sulfonylureas, omeprazole, and cisapride). Conversely, serum concentrations of the triazoles are decreased by rifampin, isoniazid, phenytoin, fosphenytoin, and carbamazepine (Albengres et al., Drug Saf, 18(2):83-97 (1998)). Griseofulvin is a CYP inducer of coumarin-like drugs and estrogens (Kojo et al., Arch Toxicol, 72:336-346 (1998)).
Antifungals and highly active antiretroviral therapy (HAART). One of the most challenging issues facing providers treating patients with human immunodeficiency virus (HIV) infection is the complex problem of drug interactions associated with highly active antiretroviral therapy (HAART). Given the effects of the protease inhibitor (PI) and non-nucleoside reverse transcriptase (NNRTI) class on the CYP450 system, metabolism drug interactions are most common and problematic when prescribing HAART. Approximately 50% of all drugs are substrates of CYP3A4, including HIV protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). Antifungal drugs (ketoconazole, itraconazole, fluconazole) and macrolides (erythromycin, clarithromycin) are CYP3A4 inhibitors and increase plasma concentrations of NNRTIs and P is (Piscitelli et al., N Engl J Med, 344:984-996 (2001)). The azole antifungal ketoconazole is a potent CYP3A4 inhibitor and increases the level of drug exposure to saquinavir and amprenavir by 190% and 31%, respectively. Conversely, ritonavir and lopinavir/ritonavir have demonstrated a three-fold increase in ketoconazole levels when used concurrently. Therefore doses >200 mg/day of ketoconazole are not recommended when using these medications concurrently. In general, ketoconazole should be avoided with concurrent HAART. The newest azole antifungal, voriconazole (Vfend), has significant activity against aspergillosis and Candida albicans, but should be closely monitored for toxicity, such as elevated transaminases and visual toxicity.
Thus, besides the classic non-polyenic antibiotics (Gottlieb et al., Ann Rev Phytopathol, 8:371-380 (1970): cycloheximide, griseufulvin, antimycin, the polyoxins, the oligomycins, and variotin), and the echinocandins, new antifungal antibiotics continue to be discovered: diazaquinomycin (Maskey et al., Nat Prod Res, 19(2):137-142 (2005)), norresistomycin and resistoflavin (Kock et al., J Antibiot (Tokyo), 58(8):530-534 (2005)), fridamycin (Maskey et al., J Antibiot (Tokyo), 56(11):942-949 (2003)) transvalencin (Hoshino et al., J Antibiot (Tokyo), 57(12):803-807 (2004)), clavariopsins—cyclic depsipeptides (Kaida et al., J Antibiot (Tokyo), 54(1):17-21 (2001)). The echinocandins are synthetic modifications of naturally produced lipopeptides; these natural lipopeptides are produced by fungi (Denning, J Antimicrob Chemother, 49:889-891 (2002)), which include aculeacin A (Aspergillus aculeatus), echinocandin B (Aspergillus rugulovalvus), pneumocandin B (Zalerion arboricola), enfumafungin (Hormonema-like fungus) and the papulacandins (Papularia sphaerosperma). On the other hand, fengycin is a lipopeptide produced by a bacterium, Bacillus subtilis (Vanittanakom et al., J Antibiot (Tokyo), 39(7):888-901 (1986)).
Because of the shortcomings of existing antifungal treatments, there is a need in the art for improved antifungal therapies having greater efficacy, bioavailability, and/or reduced side effects.